The transition from childhood to adolescence is associated with significant increases in rates of substance use disorders. There are a number of factors that may be related to these increases, including underlying psychological propensities and genetic risk factors. Recent research aimed at elucidating the genetic underpinnings of the development of SUDs is limited by the heterogeneity in their clinical presentations. There have been attempts to circumvent this problem by examining intermediary phenotypes, which may be more proximally linked to genes. Distress tolerance (DT), or the propensity to pursue goals in the face of affective distress, is a potential intermediary phenotype relevant to the emergence of SUDs. DT has been linked to risk taking and substance use in youth and to the likelihood that adults will not attempt to quit using substances and will relapse during abstinence from substances. DT is tied to emotion regulation abilities, which mature throughout adolescence. Emotional experiences during adolescence are heightened because of hormonal and neuronal changes occurring, which increase the likelihood that adolescents will engage in risky behaviors to reduce negative effect. DT plays an intimate role in this process. An examination of DT as a mediator of the relationship between genetic variation and substance use among youth might help clarify how genes influence SUDs and the role of DT within this process. Supporting this line of reasoning, previous research demonstrates the heritability of substance use problems among youth, a relationship between low DT and particular genetic polymorphisms (COMT Val158Met [rs4680], 5-HTTLPR), and a connection between low DT and substance use behaviors among youth. In the current study, we will utilize data from an ongoing 10-year longitudinal study following two cohorts of 641 youth (youth are 8-10 years-old at baseline). This study aims to examine the effects of genetic variants relevant to emotion regulation, stress response, and substance use (e.g. CRHR1, GCCR, DAT, COMT, and GABRA2) on DT (assessed via the Behavioral Indicator of Resiliency to Distress) and substance use behaviors across early and middle adolescence. It is hypothesized that genetic variation will predict lower levels of DT. Further, it is hypothesized that the effect of high-risk genes on substance use behaviors will be mediated by DT levels. This research will enhance our understanding of the relationship between genes and substance use, with the potential to provide unique intervention points to prevent or treat SUDs among youth. The main training goal for this award is to develop a programmatic line of research at the intersection of genetics, substance use, and developmental psychopathology. Training objectives include gaining knowledge of relevant genetic methodologies and developing an understanding of processes underlying substance use across adolescence.